Caspase is a new kind of cysteine protease in the form of α2β2 tetramer discovered during the last 10 years. About 14 kinds thereof have been known until now. Caspase-1(ICE), one of them, is a kind of cytokine and participates in converting the biologically inactive prointerleukin-1β to the active interleukin-1β. Interleukin-1 consists of interleukin-1α and interleukin-1β, both of which are synthesized in monocytes in the form of 31 KDa precursor. Only prointerleukin-1β is activated by ICE. The positions hydrolyzed by caspase-1 are Asp27-Gly28 and Asp116-Ala117. The hydrolysis of the latter position gives interleukin-1β. Interleukin-1β has been reported to act as an important mediator in causing inflammation (1,3). Caspase-1 has been discovered for the first time in 1989, and the three dimensional structure thereof was determined by X-ray crystallographic method by two independent study groups.
Caspase-3(CPP-32) is broadly studied for its role or mechanism for action, and its three dimensional structure was determined in 1996(2). Caspase-3(apopain) activated from procaspase-3 is hydrolyzed in the position of (P4)Asp-X-X-Asp(P1) motif, and the known substrates include poly(ADP-ribose) polymerase, U1 70,000 Mr small nuclear ribonucleoprotein, catalytic subunit of 460,000 Mr DNA-dependent protein kinase, etc. The X-ray structure of caspase-7 has been reported to be very similar to that of caspase-3(4).
Caspase-8 and 9 are present in the upstream of caspase-3,6,7, and all of these caspases are known to participate in the apoptosis cascade. The X-ray structure of caspase-8 was determined in 1999(5), and particularly the inhibitors thereof may be advantageously used for treating the diseases related to apoptosis.
Caspase inhibitors mean those compounds that inhibit the activity of caspase, and so control such symptoms as inflammation, apoptosis, etc. caused by the caspase activity. Diseases or symptoms that may be treated or attenuated by administering the inhibitors include the following: dementia, cerebral stroke, brain impairment due to AIDS, diabetes, gastric ulcer, cerebral injury by hepatitis virus, hepatitis-induced hepatic diseases, acute hepatitis, fulminant hepatic failure, sepsis, organ transplantation rejection, rheumatic arthritis, ischemic cardiac diseases, and liver cirrhosis(6).
Among the caspase inhibitors known until now, the most noted irreversible inhibitors are the following:

Both the above inhibitors exhibit their activity based on the common mechanism that they irreversibly inactivate the enzyme to suppress the cell apoptosis (irreversible, broad-spectrum inhibitor). It has been reported that irreversible inhibitor has much more effective inhibitory activity than reversible inhibitor (7). Both IDN-1965 of IDUN Co. and MX-1013 of Maxim Co. are reported to show activity in cell apoptosis model for hepatic injury (8, 9). These compounds are now in the stage of preclinical test. The irreversible inhibitor IDN-6556 is now in the stage of phase II clinical trial as a therapeutic agent for hepatic injury (10, 11).
